Mechanisms of Neuroinflammation in Experimental Cerebral Malaria

Cerebral Malaria (CM) is an encephalopathy that causes an estimated 343,000 yearly deaths as a result of Plasmodium falciparum infection. Survivors experience long-term neurological sequelae. Cerebral vascular dysfunction is well documented on autopsy of CM patients. Signs include congestion of cerebral blood vessels, adhesion of both parasites and leukocytes to the vascular endothelium, and thrombi in all verified CM patients. In addition, overt disseminated intravascular coagulopathy is seen in 19% of confirmed CM patients and triples of the likelihood of mortality from CM, while most other patients have compensated coagulopathy. High levels of inflammatory cytokines in the brain also correlate with poor outcomes, while a high ratio of the regulatory cytokine, IL-10 to inflammatory cytokines is protective. Both thrombi and fibrinogen leakage correlate with axonal damage; however, there is a critical gap in our knowledge of the role of thrombi and fibrinogen in CM pathogenesis. The role of thrombi and fibrinogen in promoting inflammation has not yet been studied in CM, though the inflammation/coagulation axis has important implications in other neuropathologies. Our objective is to investigate the intersecting roles of inflammation and coagulation.